Hormone intake by humans can occur through, inter alia, consumption of pharmaceutical compositions, foodstuffs, nutritional supplements, and nutraceuticals. Such hormones include phytoestrogens, or nonsteroidal estrogens, steroidal estrogens and progestins. Phytoestrogens comprise, for example, genistein, daidzein and glycitein, and their respective glucoside, malonylglucoside and acetylglucoside derivatives. Estrogens and progestins are known to be used for hormone replacement therapy (HRT) and in contraceptive medications. HRT with estrogens or with estrogen/progestin combinations has been the standard method for treating symptoms associated with menopause (Ernster V L et al. (1988) Benefits and Risks of Menopausal Estrogen and/or Progestin Hormone Use, Prev. Med. 17:201-223). The onset of menopause in mature adult women, which is accompanied by reduced estrogen production, is associated with an array of symptoms. These symptoms include hot and cold flashes, palpitations, dizziness, headaches, altered secretions as well as weight loss and gain. Reduced levels of circulating estrogen in post-menopausal women are also associated with increased risks of osteoporosis and coronary heart disease. Treatment protocols using estrogen alone significantly reduce the risks of cardiovascular disease and osteoporosis, if treatment begins at menopause. The protective effect of estrogen against heart disease is related to its ability to raise levels of circulating HDL and lower levels of LDL.
In contrast with this beneficial effect, long-term use of estrogens is positively correlated with an increased risk for endometrial cancer development. This risk may be reduced by simultaneous administration of a progestin, which prevents overgrowth of endometrial cells. Hence, an estrogen/progestin combined HRT protocol is recommended for a woman with an intact uterus. This form of combination therapy however, apparently diminishes the beneficial effects of estrogen on the plasma lipid profile (Lobo R. 1992. The Role of Progestins in Hormone Replacement Therapy; Am. J Obstet. Gynecol. 166:1997-2004). Furthermore, some progestins are associated with an increased risk of mammary cancer development (Staffa J. A. et al. 1991. Progestins and Breast Cancer: An Epidemiologic Review, 57: 473-491; King R. J. B. 1991. A Discussion of the Roles of Estrogen and Progestin in Human Mammary Carcinogenesis, J. Ster. Biochem. Molec. Bio. 39:8111-8118).
As disclosed in U.S. Pat. No. 5,516,528, HRT formulations have been developed which include phytoestrogens such as the soy-derived isoflavones genistein and daidzein. The health benefits of these plant products was first suggested by epidemiologic data indicating that Asian populations in which soy is a dietary staple suffer relatively low incidences of breast, uterine and other hormone-dependent cancers, ostensibly due to a high intake of soy and soy-derived products.
Although soy isoflavones have been shown to exert anti-proliferative effects in human adenocarcinoma and breast cancer cell lines in vitro, these effects occur only at relatively high, i.e. 15 molar (“M”) concentrations (Constantinou, A. I. et al. 1998. Genistin Induces Maturation of Cultured Human Breast Cancer Cells and Prevents Tumor Growth in Nude Mice, Am. J. Clin. Nutr. 68:1426s-1430s; Le Bail, J. C. et al 1998. Estrogenic and Antiproliferative Activities on MCF-7 Human Breast Cancer Cells by Flavenoids, Cancer Lett. 130:209-216). The anti-proliferative effects on cancer cells in vitro caused by phytoestrogens at such high concentrations may not have clinical relevance because the IC50 values are at least one order of magnitude greater than the blood concentrations achievable from soy-based diets.
A phytoestrogen concentration range of approximately 0.1 to 10 μM is representative of that found in healthy humans, both Asian and European, with soy-based diets. (Adlercreutz, H. et al. 1993. Plasma Concentrations of Phyto-oestrogens in Japanese Men, Lancet 342:1209-1210; Gooderham et al., 1996. A Soy Protein Isolate Rich in Genistein and Daidzein and its Effects on Plasma Isoflavone Concentrations, Platelet Aggregation, Blood Lipids and Fatty Acid Composition of Plasma Phospholipid in Normal Men, J. Nutr. 125:2000-2006). At these lower concentrations, various phytoestrogens, including genistein, counestrol, biochanin A, apigenin, luiolin, kaempferl and enterolactone, were shown to induce cell proliferation in estrogen receptor-positive, but not in estrogen receptor negative human breast cancer cell lines, thus demonstrating the estrogenic effects of these compounds (Wang, C. and Kurtzer, M. S. 1997. Phytoestrogen concentration Determines Effects on DNA synthesis in Human Breast Cancer Cells, Nutr. Cancer 28:236-247).
Hence, although phytoestrogens have been disclosed as beneficial components for HRT formulations, it has been found that the presence of phytoestrogens at levels normally found in healthy humans increases the risk for development of hormone-dependent cancers.
The carotenoid astaxanthin has been demonstrated to have anti-tumorigenic effects in vivo in rodent models (Tanaka, T. et al. 1995. Suppression of azoxymethane-induced rat colon carcinogenesis by dietary administration of naturally occurring xanthophylls astaxanthin and canthaxanthin during the postinitiation phase. Carcinogenesis 16: 2957-2963; Tanaka, T. et al. 1995. Chemoprevention of rat oral carcinogenesis by naturally occurring xanthophylls, astxanthin and canthaxanthin. Canc. Res. 55:4059-4064).
The carotenoid phytoene has also demonstrated anti-cancer activity. The cancer preventive activity of phytoene was demonstrated following introduction of the gene encoding phytoene synthase into mammalian cells normally lacking this gene. These cells acquired resistance against malignant transformation imposed by transfection of activated oncogenes (Nishino, H. 1998. Cancer prevention by carotenoids. Mutat. Res. 402:159-163).
β-carotene was the first carotenoid suggested to have anti-cancer properties (Peto et al. 1981. Carotenoids and cancer: an update with emphasis on human intervention studies, Nature 290:201-208). Epidemiological studies of β-carotene's effect on cancer, however, have produced conflicting results. Although some studies have showed that β-carotene increases the risk for developing cancer (Omenn et al., 1996. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease, N. Engl. J. Med 334:1150-1155), other cell culture and animal studies have indicated quite consistently that β-carotene has an anti-carcinogenic effect.
Lycopene, a carotenoid found in tomatoes, is strongly associated with anti-oxidant and anti-cancer activities. The anti-proliferative effects of lycopene on breast cancer cells in vitro has been shown to be mediated through interference with the IGF-1 receptor signaling pathway and cell cycle progression (Karas et al. 2000. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr. Cancer, 36:101-11). IGF-I is a growth factor obligatory for malignant transformation of breast tissue, and its concentration in plasma determines risk factor for cancers of both the breast (LeRoith, D., Werner, H., Beitner-Johnson, D. and Roberts, C. T., Jr. 1995. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr. Rev. 16:143-59; Hankison S. E. et al. 1998. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393-6) and prostate (Chan, J. M., Stampfer, M. J. Giovannucci, E., Gann, P. H., Ma, J. 1998 Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563-66).
U.S. Pat. No. 5,827,900 discloses the use of lycopene for inhibiting the growth of cancers in vitro and in vivo, including hormone-dependent endometrial and breast cancers. U.S. Pat. No. 5,827,900 requires very high carotenoid dosage levels. The '900 patent discloses 7 mg/Kg to 20 mg/Kg per day as illustrative lycopene dosages. The method of the '900 patent would thus require 490 mg-1400 mg of lycopene per day for a person weighing 70 kg (154 lbs.).
The combination of lycopene and soy isoflavones in dietary supplements has been disclosed in U.S. Pat. No. 5,904,924. The '924 patent discloses a nutritional powder composition comprising soy isoflavones (phytoestrogens) and lycopene. The '924 patent only refers to the ability of phytoestrogens to decrease the risk of estrogen dependent cancers. Nowhere does the '924 patent disclose that dietary intake of phytoestrogens incurs a risk for adverse health affects, and that such risk can be reduced by the concomitant consumption of carotenoids.
The use of phytoestrogens in dietary supplements has been disclosed in U.S. Pat. Nos. 5,830,887 and 5,807,586. The combination of carotenoid mixtures, vitamin A and phytoestrogens in dietary supplements for women was disclosed in U.S. Pat. No. 5,807,586. The dosage amounts of vitamin A and mixed carotenoids disclosed in the '586 patent range from about 400 to about 2000 μg retinol equivalents (“RE”). 1 RE is equivalent to about 6 μg beta-carotene and about 12 μg alpha-carotene or cryptoxanthin. The dosage range disclosed in the '586 patent is thus approximately equivalent to about 2.4-12 mg of beta-carotene and about 4.8-24 mg of alpha-carotene or cryptoxanthin. Since lycopene and lutein do not exhibit substantial provitamin A activity, the RE for these carotenoids cannot be calculated. The dosage levels disclosed in the '586 patent, however, are expressed only in RE units. The disclosure of the '586 patent thus does not limit dosage levels of carotenoids which do not exhibit substantial provitamin A activity, such as lycopene and lutein.
The instant invention is directed to a method and compositions useful for preventing adverse effects which may be associated with the intake of pharmaceutical compositions, foodstuffs, nutritional supplements, or nutraceuticals comprising hormones such as estrogens, phytoestrogens and progestins. Such adverse effects include, but are not limited to, the increased risk of various types of cancer. The administration of phytoestrogens has been previously disclosed as beneficial in decreasing the risks for developing cancer. It has been found, however, that intake of phytoestrogens can incur an increased risk for developing hormone-dependent cancers.
There is thus a long felt need for a method and a composition useful for preventing the adverse effects which may be associated with the intake of foodstuffs, pharmaceutical compositions, nutritional supplements, and nutraceuticals comprising phytoestrogens, steroidal estrogens, and/or progestins. A need also exists for compositions which can be used to prevent the adverse effects associated with the administration of pharmaceutical compositions containing hormones such as, for example, steroidal estrogens and progestins, without inhibiting the beneficial activity of such hormones.
It is therefore a purpose of the present invention to provide a method for inhibiting the adverse effects which may be associated with the consumption of food stuff or dietary supplements comprising phytoestrogens and progestins.
It is another purpose of the present invention to provide a composition useful for preventing the adverse effects which may be associated with the consumption of food stuff or dietary supplements comprising phytoestrogens and progestins.
It is yet a further purpose of the present invention to provide a novel hormone-comprising pharmaceutical composition with reduced side effects relating to adverse effects that the hormones may have, thus overcoming the disadvantages of the pharmaceutical composition known from the prior art.
Other objects of the invention will become apparent as the description proceeds.